Use of C1 inhibitor for the prevention of ischemia-reperfusion injury

a technology of ischemia and perfusion injury, which is applied in the direction of drug composition, peptide/protein ingredients, extracellular fluid disorder, etc., can solve the problems of infarction if not reversed, ischemia of the cerebral tissues served, and further indirect damag

Active Publication Date: 2011-12-06
PHARMING INTPROP BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]The present invention is based on the surprising finding that where naturally occurring plasma derived C1 inhibitor (C1INH), has lost most of its ability to reduce ischemia reperfusion injury in a mouse model for transient cerebral focal ischemia when administered after ischemia, a recombinant preparation of C1INH is still able to exert its neuroprotective effects also when injected at least 1 hour after ischemia and / or reperfusion. Surprisingly, a neuroprotective effect can still be reached when the C1INH is injected 18 hours after ischemia and / or reperfusion. The difference between the naturally occurring plasma derived C1INH and the recombinant preparation of C1INH is that the first has a plasma half life of at least 24 hours and is fully sialylated glycoprotein, and the latter has a reduced plasma half life and has a different glycosylation as compared to the plasma derived product.
[0005]A difference known between the naturally occurring plasma derived C1INH and the recombinant preparation of C1INH is the extent and type of glycosylation. The recombinant glycoprotein contains a broad array of different N-glycans, comprising oligomannose-, hybrid-, and complex-type structures, whereas the N-glycans of plasma derived C1INH are mainly composed of fully sialylated complex-type structures. As a result of the differences in glycosylation, the plasma derived glycoprotein has a plasma half life of at least 24 hours and the recombinant C1INH has a reduced plasma half life.
[0053]The administration of the C1INH before the foreseen occurrence of ischemia and reperfusion injury is attractive since it may prevent the occurrence of most if not all damages associated with the ischemia and reperfusion injury the same way as presented when the C1INH is administered after the occurrence of ischemia and reperfusion injury, if not better.
[0057]The effective dose, i.e. effective concentration and frequency, of the C1INH when used in the methods of the invention will depend on the specific pharmaceutical composition which is used, the severity of the condition and the general state of the patient's health. In general, the effective dose of a pharmaceutical composition which is based on a C1INH for use in the methods of the invention may be found by routine optimisation. A suitable starting point is the dose which is used for the equivalent pharmaceutical composition which is based on plasma-derived C1INH. A great advantage of a pharmaceutical composition of the invention is that a high initial dose may be used in treatment, which enhances the likelihood of successful treatment. This high initial dose is possible because the C1INH in the pharmaceutical composition of the invention shows a faster clearance than its natural counterpart. In particular for the treatment of acute cases, a high initial dose of the C1INH of the invention may be advantageous. This high initial dose may be at least 1.5, at least 2, 3 or 4 times the dose of the natural occurring counterpart which would be administered.

Problems solved by technology

A stroke occurs when such arteries are blocked by a clot or bursts and results in ischemia of the cerebral tissues that are served by the blocked artery.
Direct damage to the brain is caused by the interruption of the blood flow, mainly due to loss of oxygenation to the viable tissue, ultimately leading to infarction if not reversed.
However if the insult is reversed (either physiologically or therapeutically) then reperfusion of the ischemic tissue may paradoxically cause further indirect damage.
However, the window in time around the stroke during which administration of C1INH is therapeutically effective is rather narrow.

Method used

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  • Use of C1 inhibitor for the prevention of ischemia-reperfusion injury
  • Use of C1 inhibitor for the prevention of ischemia-reperfusion injury
  • Use of C1 inhibitor for the prevention of ischemia-reperfusion injury

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0076]Previous experiments showed that a single dose of rhC1INH (15 U / mouse) administered at the beginning of the ischemic period, significantly reduces ischemic volume, as assessed 48 hours after ischemia in our mouse model of cerebral focal ischemia in a manner very similar to plasma derived C1INH. In this Example we have explored the time window of efficacy for rhC1INH neuro-protective activity on the ischemic volume and functional deficits. We have also studied the effect of rhC1INH on seven-days outcome by assessing the neurodegeneration and glial response.

1. Methods

1.1 Transient Focal Cerebral Ischemia

[0077]Ischemia was achieved by middle cerebral artery occlusion (MCAO) as previously described (De Simoni et al., 2003 and 2004, supra). Anesthesia was induced by 5% isoflurane in N2O / O2 (70 / 30%) mixture and maintained by 1.5-2% isoflurane in the same mixture. To confirm the adequacy of the vascular occlusion in each animal, blood flow was measured by laser doppler flowmetry (Tra...

example 2

Study on the Neuroprotective Action of rhC1-INH in Mouse Models of Focal Cerebral Ischemia

[0102]We have previously demonstrated that 15 U of rhC1-INH have a marked neuroprotective action in a model of murine cerebral ischemia / reperfusion also when administrated 1 hour after the onset of ischemia / reperfusion, at variance with pdC1-INH that, at this time of post-treatment, is no longer effective. This neuroprotection is long-lasting, in fact seven days after ischemia and treatment, ischemic brains of mice treated with rhC1-INH still show a decreased infarct size. In the following experiments we have determined the time window of efficacy (beyond 1 hour post) and the dose-response of rhC1-INH neuroprotective activity on the ischemic volume. In addition we have performed a direct comparison among pdC1-INH, rabbit and cow rhC1-INH (at the most effective dose and time-points for rabbit rhC1-INH) using the same protocol.

Methods

Animals

[0103]Procedures involving animals and their care was co...

example 3

Comparison of the Ability of RHC1INH and Plasma Derived C1INH to Inhibit Activation of the Classical and MBL Pathways

Materials and Methods

[0118]The effect of rhC1NH and pdC1INH (Cetor, Sanquin, Amsterdam, The Netherlands) on the function of the classical and lectin pathway was examined in the Wieslab TM complement system Screen (Euro-Diagnostica, Malmo, Sweeden) using two different sources of serum. One serum source is included in the kit, where it is used as a positive control (hereafter referred to as serum sample 1). The other serum sample was obtained from a commercially available pool of human serum (pool of 25 different donors; Kordia, Leiden, The Netherlands), hereafter referred to as serum sample 2. Both serum samples were incubated in independent triplo's with 0, 15, 30 and 75 μmol rhC1INH or pdC1INH for 30 min at room temperature. Therefore, stock solutions of pdC1INH and rhC1INH were diluted in water to appropriate concentrations. Volumes corresponding with 15, 30 and 75 ...

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Abstract

The present invention relates to the therapeutic and prophylactic use of C1 inhibitor for preventing, reducing and treating ischemia and reperfusion injury. The C1 inhibitor of the present invention is still therapeutically effective when administered after an ischemic period and reperfusion and therefore particularly useful for unforeseen occurrences of ischemic reperfusion such as e.g. a stroke.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the therapeutic and prophylactic use of C1 inhibitor for preventing, reducing and treating ischemia-reperfusion injury, particularly cerebral ischemia-reperfusion injury that may occur as a result of a stroke.BACKGROUND OF THE INVENTION[0002]Ischemia-reperfusion injury is a well known occurring pathologic condition. It may either represent a foreseen pathologic condition or an unforeseen pathologic condition. Stroke is one of the most common types of unforeseen ischemia-reperfusion injury. Stroke is the third cause of death and the leading cause of long-term disability in industrialized countries. Stroke is a type of cardiovascular disease that affects the arteries leading to and within the brain. A stroke occurs when such arteries are blocked by a clot or bursts and results in ischemia of the cerebral tissues that are served by the blocked artery. Direct damage to the brain is caused by the interruption of the blood flow,...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K14/00
CPCA61K38/57A61K45/06A61P1/00A61P13/12A61P25/00A61P41/00A61P7/02A61P9/00A61P9/10
Inventor MANNESSE, MAURICENUIJENS, JOHANNES HENRICUSPIEPER, FRANKDE SIMONI, MARIA GRAZIAZIERE, GIJSBERTUS JOHANNES
Owner PHARMING INTPROP BV
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